The production of recombinant proteins, vaccines and antibodies with the aid of prokaryotic and eukaryotic cells plays an essential role in modern pharmaceutical production. To produce complex post-translationally modified proteins and antibodies animal derived cells are primarily used. However, the use of animal derived cells sets high demands for the fermentation process due to the specific characteristics of these cells such as e.g. the culture medium, the sensitivity towards limitation and inhibitions (for example by lactate, CO2, ammonium etc.), the sensitive outer membrane (shear stress), the low specific rates and the sensitivity towards variations in the culture conditions (e.g. due to local inhomogeneities, pH variations, pO2 variations etc.). These properties have to be taken into consideration when designing bioreactors and for process control.
In recent years various types of reactors for culturing cells have been developed. Irrespective of the type, the reactor must be able to fulfill the following basic technical functions: adequate suspension as well as homogenization, adequate material and heat transport as well as a minimal shear stress on the cells. The stirred-tank reactor is especially suitable for industrial use. In this reactor the necessary energy for fulfilling the basic functions is introduced by mechanical stirring.
In order to achieve high product titer and specification compliant product quality, the operating mode of the reactor in particular plays an important role in addition to cell line development, media composition and design of the reactor. Generally the following operating modes are employed: batch processes, fed batch processes, continuous processes with or without cell retention (for example perfusion or chemostat) as well as semi-continuous processes such as e.g. internal or external dialysis.
To prevent nutrient limitations feed solutions are added to reactor in the form of concentrated solutions (so-called fed batch processes). To avoid inhibition by end products of the cell's metabolism the products of the cell's metabolism have to be removed from the reactor or from the culture medium in the reactor. This can be carried out for example by perfusion or dialysis. In the case of dialysis one differentiates between external or internal dialysis.
EP 1 474 223 reports a dynamic mixer. An animal cell culturing device comprising a container for the uptake of a cell suspension, a device for feeding- and discharge of gas into the cell suspension, and a device for production of a current in the cell suspension is reported in DE 10 2005 053 333. Method and apparatus for cell culture is reported in EP 0 224 800. Nomura, T., et al., J. Chem. Eng. Jap. 29 (1996) 134-138 report development and mixing characteristics of folding anchor impeller for round bottom flask. An impeller draft tube agitation system for gas-liquid mixing in a stirred tank reactor is reported in WO 01/41919. In U.S. Pat. No. 4,438,074 a continuous polymerization reactor is reported. An agitation system and method for gas transfer into liquids is reported in EP-A 0 200 886. In EP-B 0 049 229 a cooking apparatus having a stirring device is reported.